Substituted monothiosemicarbazones of diformylbenzenes



Patented Dec. 29, 1953 SUBSTITUTED MONOTHIOSEMICARBA- ZONES OF DIFORMYLBENZENES Hans Schmidt, Wuppertal-Vohwinkel, and Robert Behnisch and Fritz Mietzsch, Wuppertal- Elberfeld, Germany, Industries, Inc., New York, N. Y.

No Drawing. Application February 6, 1952, Serial No. 270,268

6 Claims.

This invention relates to condensation products of thiosemicarbazones derived from phthalaldehyde and its isomers, which are found to be possessed of good antibacterial activity, especially against tubercle bacilli;

It has been found that the reaction of, at choice, one of the isomeric phthalaldehydes,with thiosemicarbazide can be conducted sothat either monothiosemicarbazones or dithiosemicarbazones are principally formed. For instance, if one of the three isomeric phthalaldehydes is reacted with thiosemicarbazide in the molar ratio of 1:2, the corresponding phthalalmonothiosemicarbazone is principally obtained. Formation of the dithiosemicarbazone under these conditions, to a large extent, may be prevented by gradually adding the thiosemicarbazide solution to the phthalaldehyde and by avoiding prolonged heatin; of the reaction mixture.

The formyl-benzalthiosemicarbazones obtainable in this manner may be further reacted with amino compounds in accordance with this invention to yield improved chemotherapeutical agents. For instance, therapeutically valuable products of this type can be obtained by using amino com- Example 1 About 27 grams of terephthalaldehyde in 750 ccs. of alcohol are refluxed and a hot solution of 18 grams of thiosemicarbazidein 250 ccs. of water is added thereto in small portions. Towards the end of this addition, precipitation starts. Prolonged heating is avoided to minimize formation of the dithiosemicarbazone by rearrangement. The hot solution is filtered from the insoluble material, which is the dithiosemicarbazone formed as by-product, and on cooling,

yellow, bright crystals precipitate from the filtrate 50 the following assignors to Schenley recrystallized from dilute alcohol or from butanol and are soluble in caustic soda to produce a yellow colored solution. The melting point of the product is about 215 C., with decomposition, and it is the monothiosemicarbazone of terephthalaldehyde, represented by the formula:

Alternatively, this intermediate product may be obtained by proceeding as follows:

A solution of 54 g. of thiosemicarbazide in 360 cc. of water and cc. of 5 N. hydrochloric acid is added, while stirring, slowly over a period of several hours to a solution of 80.4 g. of terephthalaldehyde in 1000 cc. of methanol. After a short period of time, if necessary after inoculation with a seed crystal, the terephthalal-monothiosemicarbazone begins to crystallize. When crystallization is finally completed, the precipitate is filtered off and washed withwater. The monothiosemicarbazone of terephthalaldehyde is obtained in good yield. By this procedure, merely very little of the undesired terephthalaldithiosemicarbazone is found in the product as an impurity and the monothiosemicarbazone may be easily separated from it by recrystallizing from dilute aqueous ethanol.

About 20.7 grams of terephthalaldehydemono- 'thiosemicarbazone, prepared as above described,

and 19 grams of 4-amino-benzalthiosemicarbazone, obtainable by condensing 4-aminobenzaldehyde with thiosemicarbazide in an aqueous medium (melting point 204), are refluxed in two liters of methyl alcohol. The reactant compounds remain partially dissolved temporarily, but the yellow-colored condensation product soon begins to precipitate before complete clarification of the solution occurs. Boiling of the mixture is continued for some time, and, if desired, a few drops of glacial acetic acid may be added to accelerate the reaction. After cooling the reaction mixture, the reaction product is precipitated and it is removed by filtration and washed with methyl alcohol and acetone. About 35 grams of a yellow powder are obtained which, when heated, decomposes above 260 C. This product is insoluble or difficultly soluble, in the ordinary solvents and it may be represented by formula:

in an abundant quantity. These crystals can be Similarly the compound 8,684,426 3 4 1 i a be obtained as an orange-yellow powder. and when it is condensed with p-amino-sa icyl c l 'il el i 'iillg at 25'?" C. The 4-aminobenzal acetone acid, the product obtained is that represented by thiosemicarbazone is obtainable according to our the formula: copcnding application Serial No. 217,414, flied March 24 1951 5 CH=N.NH.(C:8).NH|

Example 2 CH=N OH By reacting terephthalaldehyde-monothiosemicarbazone, prepared as described in Example 1, COOH with a substantially equimolecular quantity of 10 p-amino-salicylic acid, the compound represented by the formula: I

/\. About 20.7 grams of terephthalaldehyde-mono- UOOCT thiosemicarbazone and 20.3 grams of aminoantion 1 pyrin (1:5-dimethyl-2phenyl1-4-amino-3-pyraa meltin zolone) in 800 cc. of methano, to which a few car.) z i g gzg i ig ggf giz in aqueous drops of glacial acetic acid have been added, are

fi olntions I refluxed for several hours, while stirring, then a a1 5 V I the reaction mixture is cooled, and the reaction Example 3 product precipitated is recovered by filtration.

About 27 grams of isophthalaldehyde are dis- About 40 grams of this product, a yellow powder Example 5 solved in 750 cos. of hot alcohol, and a hot soluhaving a, melting point of 251 C., are obtained. tion of 18 grams of thiosemicarbazide in 250 ccs. It is represented by the formula,

of water containing a few drops of glacial acetic acid is added slowly thereto. After a few mm- CH? Q CS NHI utes following the addition, an almost colorless precipitate begins to form, the undesired dlthiosemicarbazone of isophthalaldehyde, which 15 N removed by filtering the hot solution, and upon l cooling the filtrate, the monothiosemicarbazone 80 of isophthalaldehyde can be obtained by procccding in a manner similar to that described in Example 1.

This product can be condensed with 4-aminobenzalthiosemicarbazone in a manner similar to terephthala-ldehyde monothiosemicarbazone as described in Example 1, or it may likewise be condensed with p-amino-salicylic acid as de- Example 6 About 31 grams of terephthalalrmonothiosemicarbazone and 25.8 grams of 4-amino-benzenesulfonamide in 1200 cc. of methonal, to which a few drops of glacial acetic acid have been added, are refluxed for 24 hours while stirring, whereupon the reaction mixture is cooled. The product reci itated is recovered as in the re edin ficl'ibed in Example yleldmgi f the exarfiples and obtained in a very good yi ld, a2 Compounds represented by the folmu 40 a yellow powder, sintering at about 250 C. It

cn=i\'.xn. o:s .r m has the formula:

Example 7 CH=N.NH.(C:S).NH: In a manner analogous ,to that described in Example 6, terephthalal-monothiosemicarbazone and 4-amino-benzenesulfonylguanidine may be CH=N condensed to yield a yellow condensation product, having a melting point of 238 0., represent- OH ed by the formula:

NH NHriLNHSOx-Q =cH cH=N-Nncs1-im Example 4 Condensation products of terephthalal-monothiosemicarbazone with 4-amino-benzenesulfon- The operations described in Examp 1 are 00 ylthiourea (melting point 218 C.), 4-amino-benpeated with phthalaldehyde (o-bis-formyl-benzenesulfonamidmpyridme (melting point zene) substituted for the terephthalaldehyde Q) and 2 (p amino benzenesulfohamido) 4 there emp oy d and the intermediate Pmductmethyl pyrimidine (melting point 245 c.) may be iormyl-benzalthiosemicarbazone, may be then prepared in the same manner The melting condensed with amino compounds to produce the points of these products are not Sharp and the desired final products. For instance, when this products begin to decom use at the tem ratures intermediate product is condensed with 4-aminoindicate p pe benzalthiosemicarbazone, the product obtained is that represented by the formula: Example 8 7o About 41.4 grams of terephthalal-monothiosemicarbazone and 12.4 grams of allyl amine are refluxed, with stirring, for 24 hours in 700 cc. of methanol, with addition of a few drops of glacial acetic acid, and the reaction product is recovered as in the preceding examples. It is obtained as a light yellow powder, melting at 175 0., and having the formula:

In the same manner, terephthalal-monothiosemicarbazone and p-amino-acetoanilide yield a yellow condensation product having a melting benzenesulfonamido-pyridine. 4-aminobenzenepoint of 239 C. (with decomposition) and being represented by the formula:

The corresponding condensation products of wherein R, is a radical selected from the group amino-compounds with phthalaldehyde-monothiosemicarbazone and with isophthalaldehyde monothioscmicarbazone may be prepared in the same manner, as indicated in Examples 3 through 8.

This application is a continuation-in-part of co-pending application Serial No. 128,023, filed November 17, 1949, by the same inventors and entitled Thiosemicarbazones, now U. S. Patent 2,600,077 issued June 10, 1952.

In certain of the following claims, the compounds of this invention are defined by generalized structural formulae, for example, by the formula:

wherein R. is the amino compound residue. It will be understood that in this definition of the invented compounds, R means all of the amino. compound molecule excepting the amino group itself. It is, therefore, the radical of one of the above disclosed amine reactants which may be defined as being selected from the group consisting of 3-hydroxy-4-carboxyphenyl, 4-(thiosemicarbazonomethylidene)phenyl, antipyrinyl,

4-sulfamylphenyl, 4-(guanyliminosulfonyl) phen-. c5

ureidosulfonyl) phenyl,

consisting of 3-hydroxy-4-carboxyphenyl, 4-(thiosemicarbazonomethylidine)phenyl, antipyrinyl, 4-sulfamylphenyl, 4-(guanyliminosulfonyl)phenyl, 4-(2'-pyridyliminosulfonyl) phenyl, 4- (thio- 4-(4'-methylpyrimidyl- 2'-iminosulfonyl) -phenyl, allyl and 4-acetamidophenyl.

2. A compound represented by the formula:

3. A compound represented by the formula:

4. A compound represented by the formula:

5. A compound represented by the formula:

nosalicylic acid, 4-aminobenzalthiosemicarbazone, aminoantipyrlne, 4-aminobenzenesulfonamide, 4-aminobenzenesulfoguanidine, 4-amino- 6. A, compound represented by the formula:

cH=N.Nn.o :s).Nm

H=N.CH|CH=CH:

HANS SCHMIDT.

ROBERT BEHNISCH.

FRITZ MIETZSCH.

References Cited in the file of this patent Behnisch et 9.1., Angewandte Chemie," vol. 60. May 1948, pp. 1l3-5. 

1. A CONDENSATION PRODUCT OF P-FORMAYL-BENZALTHIOSEMICARBAZONE AND A PRIMARY AMINO COMPOUND CHOSEN FROM THE GROUP CONSISTING OF AMINOSALICYLIC AICD, 4-AMINOBENZALTHIOSEMICARBAZONE, AMINOANTIPYRINE, J-AMINOBENZENESULFONAMIDE, 4-AMINOBENZENESULFOGUANIDINE, 4-AMINOBENZENESULFONAMIDO-PYRIDINE, 4-AMINOBENZENESULFOTHIOUREA, 2-(P-AMINOBENZENESULFONAMIDO)4-METHYLPYRIMIDINE, ALLYL AMINE AND P-AMINOACETANILIDE; THAT IS REPRESENTED BY THE FORMULA: 